This project consists of several overlapping comprehensive, multidisciplinary population-based cohort and/or case-control studies to quantify the association between cancer-causing viruses (oncoviruses) with linked cancers. The projects include the HIV-AIDS Cancer Match (HACM) Study that links some 780,000 people with HIV-AIDS in 14 U.S. states and metropolitan regions with cancer registry data to examine cancer risk among HIV-infected individuals and the Transplant Cancer Match (TCM) Study that links some 175,000-transplant recipients to cancer registry data in 13 cancer for comparative studies. In addition, focused projects on BL include the Ghana BL Study and the EMBLEM Study with broad goals to study the role of infections, including HIV, immune responses to EBV and Plasmodium falciparum malaria and genetic susceptibility in the etiology to BL. The studies focus on the role of the role of immunological alteration, infection and risk for cancer, including BL, NHL, Hodgkin lymphoma, Kaposi sarcoma, lung cancer, cervical cancer, head and neck cancer, testicular cancer, breast cancer, penile cancer, and gastric cancer. Biological specimens (peripheral blood, saliva, tumor tissues), when available, are used to measure load of infectious agents, including HIV, EBV, and KSHV, also called HHV8, Pf malaria and genetic variation in the pathogens a or the host to characterize association of biomarkers with cancer. Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses. Study of the US HACM provides continuing evidence of strong and durable impact of HIV on cancer risk in HIV infected persons. Using cancer incidence rates for the United States HIV-infected and general populations and applying Poisson models to linked HIV and cancer registry data and from Surveillance, Epidemiology, and End Results program data, an estimated 7760 (95% confidence interval [CI] = 7330 to 8320) cancers occurred in 2010 among HIV-infected people. Of these, 3920 cancers (95% CI = 3480 to 4470) or 50% (95% CI = 48 to 54%) were in excess of expected. The most common excess cancers were non-Hodgkin's lymphoma (NHL; n = 1440 excess cancers, occurring in 88% excess), Kaposi's sarcoma (KS, n = 910, 100% excess), anal cancer (n = 740, 97% excess), and lung cancer (n = 440, 52% excess). The proportion of excess cancers that were AIDS defining (ie, KS, NHL, cervical cancer) declined with age and time since AIDS diagnosis (both P .001). For anal cancer, 83% of excess cases occurred among men who have sex with men, and 71% among those living five or more years since AIDS onset. Among injection drug users, 22% of excess cancers were lung cancer, and 16% were liver cancer. An analysis of risk of cancers associated with infection persons diagnosed HIV in the United States in 2008 showed that 40% (95% CI 39-42) of the cancers are attributable to an infection, particularly Kaposi sarcoma herpes virus, Epstein-Barr virus, and human papillomavirus, which together were responsible for 90% of the new cancers (mainly Kaposi sarcoma, lymphomas, and ano-genital cancers). The infection attributable fraction was highest in the age group 20-29 years (69%, 95% CI 65-72) and in men who have sex with men (48%, 95% CI 46-50). Further analysis of data from HACM also showed that HIV-infected patients with cancer experienced higher cancer-specific mortality than in HIV-uninfected patients, regardless of the cancer stage or receipt of cancer treatment. A study to investigate the role of protective immunity to Plasmodium falciparum (Pf) malaria in Burkitt lymphoma (BL) using data from Ghana was completed. Cases were children with Burkitt lymphoma enrolled in Ghana during 1965-1994 and controls were healthy children from the same village as the cases. Malaria immunity was measured using novel antibodies to HRP-II (an antigen believed to mark recent malaria) and Pf SE36 (thought to be protective) in 354 cases and 384 matched controls. BL was positively associated with HRP-II seropositivity (OR = 1.60; 95% CI 1.08-2.36) and inversely associated with SE36 seropositivity (OR = 0.37; 95% CI = 0.21-0.64) after control for confounding factors. Furthermore, BL risk was 21 times higher (95% CI = 5.8-74) in HRP-II-seropositive and SE36-seronegative responders compared with HRP-II-seronegative and SE36-seropositive responders, suggesting that individuals with evidence of recent malaria who lack protective antibodies are at highest risk for this disease. Using a sensitive and specific 24 SNP Pf molecular-barcode array developed by the Broad Institute, BL cases from Malawi were shown to have greater genetic diversity than non-BL cancers from Malawi (mean genetic diversity score: 153.9 [se=5.8] versus 133.1 [se=7.7], t-test p=0.036). This suggested that there is a positive correlation between genetic diversity score of Pf malaria infection in BL in Malawi, shedding new light on how infections might drive risk for an AIDS defining cancer such as BL. In studies focusing on BL tumor tissues, study novel mutations were discovered in the transcription factor TCF3 (E2A), its negative regulator ID3. The mutations in TCF3/ID3 were present in about 70% of HIV-associated and sporadic BL and 40% of endemic BL, while mutations in CCND3, which codes for proteins that drive cell cycle progression were present in 38% of sporadic BL, but in only 1.8% of endemic BL. These results point to novel pathways for BL pathogenesis, which can be targeted rational design of simpler and less toxic treatment for BL. To understand the role of EBV in BL in the US, 91 confirmed BL tissues from the SEER Residual Tissue Repository (SRTR)were studied by tissue microarray (TMA). About one-third of the BL cases were EBV tumor positive. EBV positivity was lowest in cases aged 20 years and 60 years, higher in Blacks/Hispanics compared to Whites, and higher HIV positive cases compared to those who were HIV negative. These results suggest that EBV positive and EBV negative BL are distinct types whose distribution is different in different demographic groups.